Project Summary/Abstract Chronic cocaine use is among the most difficult substance-use disorders to treat. High relapse rates are likely due to a combination of limbic and cognitive factors, including vulnerability to salient limbic cues and loss of executive control. This may be due to elevated functional connectivity in limbic neural circuitry (e.g. between the medial prefrontal cortex (MPFC) and ventral striatum) and/or lower functional connectivity in executive control circuitry (e.g. between the dorsolateral prefrontal cortex (DLPFC) and dorsal striatum). The overarching goal for this proposal is to investigate the functional and structural connectivity in executive and limbic circuits among treatment-seeking chronic cocaine users versus non-drug using controls. Although many task-based functional neuroimaging studies have documented alterations limbic and executive circuitry among cocaine users, this traditional approach to neuroimaging is dependent upon participants exerting equivalent effort and attention to the task. Through the use of non-invasive transcranial magnetic stimulation (TMS) in the MR environment however, it is possible to probe activity in these circuits without relying on task performance. This will be achieved by non-invasive stimulation of the MPFC (a node in the limbic circuit) and the DLPFC (a node in the executive processing circuit). The relevance of this functional connectivity to alterations in neural structural will be investigated through the use of diffusion kurtosis imaging (Aim2). Finally we will determine the extent to which functional and structural connectivity within the limbic and executive circuits is related to drug cue-reactivity, cognitive performance, and retention in a treatment program. The results of these Aims will illuminate the relative contribution of limbic versus executive circuit dysfunction in treatment seeking cocaine users, and how that related to behavioral impairment and treatment success. This information can then be used to develop new treatment strategies directed at modulating activity in these circuits (e.g with therapeutic TMS) to improve outcomes in traditional treatment programs.